T cell-derived lymphotoxin regulates liver regeneration.
OBJECTIVE
The ability of the liver to regenerate hepatic mass is essential to withstanding liver injury. The process of liver regeneration is tightly regulated by distinct signaling cascades involving components of the innate immune system, cytokines, and growth factors. However, the role of the adaptive immune system in regulation of liver regeneration is not well-defined. The role of adaptive immune system in liver regeneration was investigated in lymphocyte-deficient mice and in conditional lymphotoxin-deficient mice.


METHODS
A model of liver regeneration after 70% partial hepatectomy was used, followed by examination of liver pathology, survival, DNA synthesis, and cytokine expression.


RESULTS
We found that mice deficient in T cells show a reduced capacity for liver regeneration following partial hepatectomy. Furthermore, surface lymphotoxin, provided by T cells, is critical for liver regeneration. Mice specifically deficient in T-cell lymphotoxin had increased liver damage and a reduced capacity to initiate DNA synthesis after partial hepatectomy. Transfer of splenocytes from wild-type but not lymphotoxin-deficient mice improved liver regeneration in T cell-deficient mice. We found that an agonistic antibody against the lymphotoxin beta receptor was able to facilitate liver regeneration by reducing liver injury, increasing interleukin-6 production, hepatocyte DNA synthesis, and survival of lymphocyte-deficient (Rag) mice after partial hepatectomy.


CONCLUSIONS
The adaptive immune system directly regulates liver regeneration via a T cell-derived lymphotoxin axis, and pharmacological stimulation of lymphotoxin beta receptor might represent a novel therapeutic approach to improve liver regeneration.
Tumanov
Alexei V
AV
Department of Pathology, The University of Chicago, Chicago, Illinois 60637, USA.
Koroleva
Ekaterina P
EP
Christiansen
Peter A
PA
Khan
Mehtab A
MA
Ruddy
Matthew J
MJ
Burnette
Byron
B
Papa
Salvatore
S
Franzoso
Guido
G
Nedospasov
Sergei A
SA
Fu
Yang-Xin
YX
Anders
Robert A
RA
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D006498:Hepatectomy; D007107:Immune System / Q000502:physiology; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D008115:Liver Regeneration / Q000502:physiology*; D053259:Lymphotoxin beta Receptor / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000378:metabolism*; D053308:Lymphotoxin-beta / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000166:cytology
D015850:Interleukin-6; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse